PROJECT SUMMARY Cocktails of antiretroviral drugs (ART) have been successful in reducing viremia to undetectable levels in HIV+ adult subjects who have access to them and who can remain adherent. Yet, the suppressive drugs are unable to eliminate latent virus in cellular and tissue compartments and are thus required for continued remission. While ART is the standard of care for HIV+ mothers and their infants who are exposed to infection risk before, during, and after birth, it has not been possible to test the impact on viral reservoirs upon treatment interruption. We have developed a robust, reproducible nonhuman primate (NHP) model for transmission in utero, peripartum and breastfeeding, in order to examine new therapeutic regimens for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Passively transferred bNAbs can provide sterilizing immunity when used as PrEP in nonhuman primate models, and have also been recently shown to prevent the establishment of viral reservoirs when given as PEP within days of viral exposure. Studies designed to understand the mechanism of action of antibodies is a critical next step. The central hypothesis of this research proposal is that novel, orthogonal therapeutic treatment with ART, a CCR5-blocking antibody, and potent neutralizing human monoclonal antibodies (bNAbs) will result in highly controlled viremia and undetectable viral reservoirs in babies born to HIV-infected mothers. Newborn and infant rhesus macaques when infected orally with SHIVSF162P3 develop widely dispersed and rapidly diverging viral quasispecies in blood and tissues within the first few days to weeks of infection, resulting in high and persistent viremia. However, in newborn macaques that receive ART or bNAbs at 24-30 hours after exposure, permanent viral seeding is prevented, but delays in treatment result in rebound upon treatment cessation. The project will explore the effects of combination and sequential treatment with ART, Leronlimab, and bNAbs, which we predict will result in prevention of viral reservoir establishment when used as PrEP, and in reduction or elimination of viral reservoirs when used as PEP in the first few weeks after virus exposure. We will show the effects of reduced infectious centers by in vivo imaging with positron emission tomography and compare these results with standard virological assays and RNAscope imaging. Ulimately, we hope that this combination therapy will lead to translation into the clinic so that HIV-exposed and vertically infected babies can be treated for limited periods of time and experience durable viral remission without further treatment.